Z-DNA is one of the many possible double helical structures of DNA. It is a left-handed double helical structure in which the double helix winds to the left in a zig-zag pattern (instead of to the right, like the more common B-DNA form). Z-DNA is thought to be one of three biologically active double helical structures along with A- and B-DNA.
Left handed DNA was first discovered by Robert Wells and colleagues, during their studies of a repeating polymer of inosine-cytosine. They observed a "reverse" circular dichroism spectrum for such DNAs, and interpreted this (correctly) to mean that the strands wrapped around one another in a left handed fashion. The relationship between Z-DNA and the more familiar B-DNA was indicated by the earlier work of Pohl and Jovin, who showed that the ultraviolet circular dichroism of poly(dG-dC) was nearly inverted in 4 M sodium chloride solution. The suspicion that this was the result of a conversion from B-DNA to Z-DNA was confirmed by examining the raman spectra of these solutions and the Z-DNA crystals. Subsequently, a crystal structure of "Z-DNA" was published which turned out to be the first single-crystal X-ray structure of a DNA fragment (a self-complementary DNA hexamer d(CG)3). It was resolved as a left-handed double helix with two anti-parallel chains that were held together by Watson-Crick base pairs (see: x-ray crystallography). It was solved by Andrew Wang, Alexander Rich, and co-workers in 1979 at MIT. The crystallisation of a B- to Z-DNA junction in 2005 provided a better understanding of the potential role Z-DNA plays in cells. Whenever a segment of Z-DNA forms, there must be B-Z junctions at its two ends, interfacing it to the B-form of DNA found in the rest of the genome.
In 2007, the RNA version of Z-DNA, Z-RNA, was described as a transformed version of an A-RNA double helix into a left-handed helix. The transition from A-RNA to Z-RNA, however, was already described in 1984.
Z-DNA is quite different from the right-handed forms. In fact, Z-DNA is often compared against B-DNA in order to illustrate the major differences. The Z-DNA helix is left-handed and has a structure that repeats every 2 base pairs. The major and minor grooves, unlike A- and B-DNA, show little difference in width. Formation of this structure is generally unfavourable, although certain conditions can promote it; such as alternating purine-pyrimidine sequence (especially poly(dGC)2), negative DNA supercoiling or high salt and some cations (all at physiological temperature, 37°C, and pH 7.3-7.4). Z-DNA can form a junction with B-DNA (called a "B-to-Z junction box") in a structure which involves the extrusion of a base pair. The Z-DNA conformation has been difficult to study because it does not exist as a stable feature of the double helix. Instead, it is a transient structure that is occasionally induced by biological activity and then quickly disappears.
Predicting Z-DNA structure
It is possible to predict the likelihood of a DNA sequence forming a Z-DNA structure. An algorithm for predicting the propensity of DNA to flip from the B-form to the Z-form, ZHunt, was written by Dr. P. Shing Ho in 1984 (at MIT). This algorithm was later developed by Tracy Camp, P. Christoph Champ, Sandor Maurice, and Jeffrey M. Vargason for genome-wide mapping of Z-DNA (with P. Shing Ho as the principal investigator).
Z-Hunt is available at Z-Hunt online.
While no definitive biological significance of Z-DNA has been found, it is commonly believed to provide torsional strain relief (supercoiling) while DNA transcription occurs. The potential to form a Z-DNA structure also correlates with regions of active transcription. A comparison of regions with a high sequence-dependent, predicted propensity to form Z-DNA in human chromosome 22 with a selected set of known gene transcription sites suggests there is a correlation.
Toxic effect of ethidium bromide on trypanosomas is caused by shift of their kinetoplastid DNA to Z-form. The shift is caused by intercalation of EtBr and subsequent loosening of DNA structure that leads to unwinding of DNA, shift to Z-form and inhibition of DNA replication.
Z-DNA formed after transcription initiation
The first domain to bind Z-DNA with high affinity was discovered in ADAR1 using an approach developed by Alan Herbert. Crystallographic and NMR studies confirmed the biochemical findings that this domain bound Z-DNA in a non-sequence-specific manner. Related domains were identified in a number of other proteins through sequence homology. The identification of the Z-alpha domain provided a tool for other crystallographic stuides that lead to the characterization of Z-RNA and the B-Z junction. Biological studies suggested that the Z-DNA binding domain of ADAR1 may localize this enzyme that modifies the sequence of the newly formed RNA to sites of active transcription.
In 2003, Biophysicist Alexander Rich of the Massachusetts Institute of Technology noticed that a poxvirus virulence factor, called E3L that has a Z-alpha related domain, mimicked a mammalian protein that binds Z-DNA. In 2005, Rich and his colleagues pinned down what E3L does for the poxvirus. When expressed in human cells, E3L increases by five- to 10-fold the production of several genes that block a cell's ability to self-destruct in response to infection.
Rich speculates that the Z-DNA is necessary for transcription and that E3L stabilizes the Z-DNA, thus prolonging expression of the anti-apoptotic genes. He suggests that a small molecule that interferes with the E3L binding to Z-DNA could thwart the activation of these genes and help protect people from pox infections.
Comparison geometries of some DNA forms
|Repeating unit||1 bp||1 bp||2 bp|
|Inclination of bp to axis||+19°||−1.2°||−9°|
|Rise/bp along axis||2.3 Å (0.23 nm)||3.32 Å (0.332 nm)||3.8 Å (0.38 nm)|
|Pitch/turn of helix||28.2 Å (2.82 nm)||33.2 Å (3.32 nm)||45.6 Å (4.56 nm)|
|Mean propeller twist||+18°||+16°||0°|
|Glycosyl angle||anti||anti||C: anti,
|Sugar pucker||C3'-endo||C2'-endo||C: C2'-endo,
|Diameter||23 Å (2.3 nm)||20 Å (2.0 nm)||18 Å (1.8 nm)|
- Mitsui et al. (1970). "Physical and enzymatic studies on poly d(I-C)-poly d(I-C), an unusual double-helical DNA". Nature (London) 228 (5277): 1166–1169. PMID 4321098.
- Pohl, F. M. and Jovin, T. M. Salt-induced co-operative conformational change of a synthetic DNA: equilibrium and kinetic studies with poly(dG-dC). J. Mol. Biol. 67, 375 - 396 (1972). PMID: 5045303
- Thamann, T. J., Lord, R. C., Wang, A. H. J. & Rich, A. High salt form of poly(dG-dC)•poly(dG-dC) is left handed Z-DNA: raman spectra of crystals and solutions. Nucl. Acids Res. 9, 5443–5457 (1981). PMID: 7301594
- Wang AHJ, Quigley GJ, Kolpak FJ, Crawford JL, van Boom JH, Van der Marel G, Rich A (1979). "Molecular structure of a left-handed double helical DNA fragment at atomic resolution". Nature (London) 282 (5740): 680–686. Bibcode:1979Natur.282..680W. doi:10.1038/282680a0. PMID 514347.
- Ha SC, Lowenhaupt K, Rich A, Kim YG, Kim KK (2005). "Crystal structure of a junction between B-DNA and Z-DNA reveals two extruded bases". Nature 437 (7062): 1183–1186. Bibcode:2005Natur.437.1183H. doi:10.1038/nature04088. PMID 16237447.
- Placido D, Brown BA 2nd, Lowenhaupt K, Rich A, Athanasiadis A (2007). "A left-handed RNA double helix bound by the Zalpha domain of the RNA-editing enzyme ADAR1". Structure 15 (4): 395–404. doi:10.1016/j.str.2007.03.001. PMC 2082211. PMID 17437712.
- Hall K, Cruz P, Tinoco I Jr, Jovin TM, van de Sande JH (October 1984). "'Z-RNA'--a left-handed RNA double helix". Nature 311 (5986): 584–586. Bibcode:1984Natur.311..584H. doi:10.1038/311584a0. PMID 6482970.
- de Rosa M, de Sanctis D, Rosario AL, Archer M, Rich A, Athanasiadis A, Carrondo MA (2010-05-18). "Crystal structure of a junction between two Z-DNA helices". Proc Natl Acad Sci USA 107 (20): 9088–9092. Bibcode:2010PNAS..107.9088D. doi:10.1073/pnas.1003182107. PMC 2889044. PMID 20439751.
- Zhang H, Yu H, Ren J, Qu X (2006). "Reversible B/Z-DNA transition under the low salt condition and non-B-form polydApolydT selectivity by a cubane-like europium-L-aspartic acid complex". Biophysical Journal 90 (9): 3203–3207. Bibcode:2006BpJ....90.3203Z. doi:10.1529/biophysj.105.078402. PMC 1432110. PMID 16473901.
- Ho PS, Ellison MJ, Quigley GJ, Rich A (1986). "A computer aided thermodynamic approach for predicting the formation of Z-DNA in naturally occurring sequences". EMBO Journal 5 (10): 2737–2744. PMC 1167176. PMID 3780676.
- Champ PC, Maurice S, Vargason JM, Camp T, Ho PS (2004). "Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation". Nucleic Acids Res. 32 (22): 6501–6510. doi:10.1093/nar/gkh988. PMC 545456. PMID 15598822.
- Rich A, Zhang S (2003). "Timeline: Z-DNA: the long road to biological function". Nature Reviews Genetics 4 (7): 566–572. doi:10.1038/nrg1115. PMID 12838348.
- Roy Chowdhury, Arnab; Bakshi, Rahul; Wang, Jianyang; Yildirir, Gokben; Liu, Beiyu; Pappas-Brown, Valeria; Tolun, Gökhan; Griffith, Jack D.; Shapiro, Theresa A.; Jensen, Robert E.; Englund, Paul T.; Ullu, Elisabetta (16 December 2010). "The Killing of African Trypanosomes by Ethidium Bromide". PLoS Pathogens 6 (12): e1001226. doi:10.1371/journal.ppat.1001226.
- Herbert A, Rich A (1993). "A method to identify and characterize Z-DNA binding proteins using a linear oligodeoxynucleotide". Nucleic Acids Res 21 (11): 2669–72. doi:10.1093/nar/21.11.2669. PMC 309597. PMID 8332463.
- Herbert A, Alfken J, Kim YG, Mian IS, Nishikura K, Rich A (1997). "A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase.". Proc Natl Acad Sci USA 94 (16): 8421–6. Bibcode:1997PNAS...94.8421H. doi:10.1073/pnas.94.16.8421. PMC 22942. PMID 9237992.
- Herbert A, Schade M, Lowenhaupt K, Alfken J, Schwartz T, Shlyakhtenko LS, Lyubchenko YL, Rich A (1998). "The Zalpha domain from human ADAR1 binds to the Z-DNA conformer of many different sequences". Nucleic Acids Res 26 (15): 2669–72. doi:10.1093/nar/26.15.3486. PMC 147729. PMID 9671809.
- Schwartz T, Rould MA, Lowenhaupt K, Herbert A, Rich A (1999). "Crystal structure of the Zalpha domain of the human editing enzyme ADAR1 bound to left-handed Z-DNA". Science 284 (5421): 1841–5. doi:10.1126/science.284.5421.1841. PMID 10364558.
- Schade M, Turner CJ, Kühne R, Schmieder P, Lowenhaupt K, Herbert A, Rich A, Oschkinat H (1999). "The solution structure of the Zalpha domain of the human RNA editing enzyme ADAR1 reveals a prepositioned binding surface for Z-DNA". Proc Natl Acad Sci USA 96 (22): 2465–70. Bibcode:1999PNAS...9612465S. doi:10.1073/pnas.96.22.12465. PMC 22950. PMID 10535945.
- Herbert A, Rich A (2001). "The role of binding domains for dsRNA and Z-DNA in the in vivo editing of minimal substrates by ADAR1". Proc Natl Acad Sci USA 98 (21): 12132–7. Bibcode:2001PNAS...9812132H. doi:10.1073/pnas.211419898. PMID 11593027.
- Halber D (1999-09-11). "Scientists observe biological activities of 'left-handed' DNA". MIT News Office. Retrieved 2008-09-29.
- Kim YG, Muralinath M, Brandt T, Pearcy M, Hauns K, Lowenhaupt K, Jacobs BL, Rich A (2003). "A role for Z-DNA binding in vaccinia virus pathogenesis". Proc Natl Acad Sci USA 100 (12): 6974–6979. Bibcode:2003PNAS..100.6974K. doi:10.1073/pnas.0431131100. PMC 165815. PMID 12777633.
- Kim YG, Lowenhaupt K, Oh DB, Kim KK, Rich A (2004). "Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo: Implications for development of a therapy for poxvirus infection". Proc Natl Acad Sci USA 101 (6): 1514–1518. Bibcode:2004PNAS..101.1514K. doi:10.1073/pnas.0308260100. PMC 341766. PMID 14757814.
- Sinden, Richard R (1994-01-15). DNA structure and function (1st ed.). Academic Press. p. 398. ISBN 0-126-45750-6.
- Rich A, Norheim A, Wang AHJ (1984). "The chemistry and biology of left-handed Z-DNA". Annual Review of Biochemistry 53 (1): 791–846. doi:10.1146/annurev.bi.53.070184.004043. PMID 6383204.
- Ho PS (1994-09-27). "The non-B-DNA structure of d(CA/TG)n does not differ from that of Z-DNA". Proc Natl Acad Sci USA 91 (20): 9549–9553. Bibcode:1994PNAS...91.9549H. doi:10.1073/pnas.91.20.9549. PMC 44850. PMID 7937803.